Figure 1. Skilled forelimb reaching performance after MCAO recovers to preoperative performance after AMPH/ENR+FA. A, Time course—all animals enrolled in the study achieved the preoperative criteria of an average of 16 successes in 20 attempts for 3 days before surgery. At Day 2 postoperatively, before any treatment, the mean deficit in reaching was not significantly different among groups (F5,49=0.684, P=0.64). AMPH/ENR+FA produced a significant overall enhancement in reaching performance compared with all other groups (*P<0.05, one-way repeated-measures ANOVA followed by Student-Newman-Keuls). VEH/ENR and VEH/ENR+FA were also significantly better than VEH/CON (#P<0.05, Student-Newman-Keuls). B, End point analysis—at 8 weeks after MCAO, reaching performance in AMPH/ENR+FA was significantly better than all other groups (*P<0.05, 2-way ANOVA followed by Student-Newman-Keuls). A 2-way repeated-measures ANOVA indicated that all groups except AMPH/ENR+FA-treated animals still displayed significant deficits in reaching when compared with preoperative performance (+P<0.001, Student-Newman-Keuls), which demonstrates that only AMPH/ENR+FA induced a recovery to baseline performance in the forelimb reaching task. Data represent the mean±SEM for the indicated number of animals/group.

Figure 2. Ladder rung walking performance after MCAO recovers to preoperative performance after AMPH/ENR+FA. A, Time course—At Day 2 postoperatively, before any treatment, the mean deficit in skilled forelimb placement was not significantly different among groups (F5,49=1.15, P=0.35). AMPH/ENR+FA produced a significant overall enhancement in ladder walk performance compared with all other groups (*P<0.001, one-way repeated-measures ANOVA followed by Student-Newman-Keuls). B, End point analysis—at 8 weeks after MCAO, ladder walk performance in AMPH/ENR+FA was significantly better than all other groups (*P<0.05, 2-way ANOVA followed by Student-Newman-Keuls) with the exception of AMPH/ENR (P=0.05). A 2-way repeated-measures ANOVA indicated that only animals receiving AMPH/ENR or AMPH/ENR+FA achieved end point performance that was not different from preoperative levels, whereas all other groups still displayed significant deficits when compared with preoperative performance (+P<0.05, Student-Newman-Keuls). Data represent the mean±SEM for the indicated number of animals/group.

Figure 3. AMPH/ENR+FA treatment after MCAO enhances corticorubral plasticity that correlates with impaired forelimb function. A, Scheme of the new projection from the intact primary motor cortex to the contralateral (dashed lines) red nucleus. The anterograde tracer BDA was injected into the contralesional sensorimotor cortex. B, Corticorubral projection after MCAO in a VEH/CON animal shows scarce BDA-positive fibers crossing the midline (dashed line) to the denervated side (right). C, AMPH/ENR+FA induced many midline BDA-positive crossing fibers and an increased innervation pattern to the side denervated by the lesion (right). D, Quantification of midline-crossing fibers in the area of the red nucleus normalized to the total labeled cerebral peduncle fibers (to correct for differences in the tracing). **P<0.01; one-way ANOVA. Midline-crossing fibers at the level of the red nucleus was plotted against performance in the forelimb reaching task (E) and ladder rung walk (F) at 8 weeks. Linear regression analysis showed a significant correlation of corticorubral fiber crossing and forelimb function. RN, red nucleus. Scale bars in (B) and (C)=50 μm. Error bars indicate SE.